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PubMed1988

Studies on aziridine derivatives. III. Synthesis and immunopharmacological activity of aziridine derivatives of propionic acid.

Several new aziridine derivatives of propionic acid were synthesized (10-15, 19, 20). o-, m-, p-Chloroanilide of chloroacetic acid 1-3 and chloride of 3-/p-chlorobenzoyl/acrylic acid 16 were the substrates. The compounds 1-3 in reaction with nicotine aldehyde or p-chlorobenzaldehyde were transformed into appropriate anilides of 2,3-epoxypropionic acid 4-9. These, in turn reacted with ethylenimine giving the appropriate 3-aziridine derivatives 10-15. Acid chloride 16 in reaction with amines gave the appropriate amides 17 and 18 which formed 2-aziridine derivatives 19 and 20 when under the influence of ethylenimine. Pharmacological analysis revealed that the aziridine derivatives 12-15, 19 and 20 modulate some immunological reactions with the prevailing effect of the suppressive component (PFC, RFC, IgM level, cellular response to SRBC). The stimulatory effect was observed with some compounds on the level of circulating IgG and GvH reaction. The mechanism of these compounds consists in their interference with the activity of Ts cells and mediators of the immunological reactions.

Animals↗
PubMed1988

[An anticancer drug--carboquone].

Carboquone (CQ) is an anticancer alkylating agent synthesized and developed by Arakawa et al. (Sankyo Co, Ltd.) in 1970, having chemical structure, 2,5-bis-(1-aziridinyl)-3-(2-carbamoyloxy-1-methoxyethyl)-6-methyl- 1,4- benzoquinone. The antitumor efficacies of CQ were reported as excellent, however, the side effects are considerably strong. For the purpose to increase the effectiveness and to eliminate the side effect, various treatment regimen with CQ have been reported. Combination chemotherapies including CQ and cis-Platinum etc. have been reported to increase the antineoplastic activity and CQ combined with immunopotentiator or prednisone have been reported to diminish the side effects. The regimens of PPQ therapy in our department is as follows. CQ is given 7 mg/m2 iv on day 1; cis-Platinum 20 mg/body, drip infusion on day 1-5. Prednisone 3.0 mg p.o. on day 1-5. The response rate found in this regimen was about 30% so far. Antitumor spectrum of this drug has been reported to become broad.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Specific inhibition of aspartase by S-2,3-dicarboxyaziridine.

Aspartase of Escherichia coli was inhibited in a competitive manner by S-2,3-dicarboxyazirdine (DCAZ), an antibacterial substance against Aeromonas salmonesida. The inhibition constant (Ki) was 55 microM, which was as low as less than one tenth that of the Km value for the substrate, L-aspartate. In view of the fact that both aspartase and fumarase (J. Greenhut et al. (1985) J. Biol. Chem. 260, 6684-6686) were inhibited by DCAZ in competitive manners, common features of the reaction mechanism of the two enzymes were discussed.

Ammonia-Lyases↗
PubMed1988

[Characteristics of the mutagenic and toxic effects of ethylene imine and its oligomers. Comparative study in the automated SOS-chromotest system and in standard bacterial test systems].

Raising total positive charge of a chemical mutagen does increase its local concentration in the area of biological target-DNA, and, as a consequence, causes increase in the rate of interaction of a mutagen with the target. Experimental evidence of this idea has been obtained in three test systems: the Ames test, Trp+ reversions in Escherichia coli WP2 and in the automated "SOS-chromotest" system with E. coli PQ 37 ("Labsystems", Finland).

Aziridines↗
PubMed1987

[Clinical results of a randomized controlled trial on the effect of adjuvant immunochemotherapy using Esquinon and Krestin in patients with curatively resected gastric cancer--7-year survival--Cooperative Study Group for Cancer Immunochemotherapy, Tokai Gastrointestinal Oncology Group].

A randomized controlled study was carried out on curatively resected gastric cancer patients in a cooperative study involving 16 institutions in order to evaluate the effect of an alternative long-term adjuvant immunochemotherapy using Esquinon (CQ) and Krestin (PSK). One week after surgery, CQ was given at a dose of 2mg/m2 once a week for 3 weeks and this was repeated every 6 weeks. CQ was administered intravenously in the 1st course and thereafter orally up to 9 courses. Three postoperative week, immunotherapy was then started in which PSK was given orally in 3 divided doses of 2g/m2/day from the day when CQ therapy ended for 4 consecutive weeks, and this performed for every course. Estimated survival rate and cumulative survival curves were compared utilizing the data up to 7 years after surgery in the chemotherapy group given CQ alone and in the immunochemotherapy group given CQ + PSK. The survival curve in all cases showed a favorable form in the CQ + PSK group for up to 36 months, and thereafter it crossed with that of the CQ group for up to 68 months. Both curves twisted at 68 months and then deviated from each other, showing that the effect in the CQ + PSK group beneficial. The curve showed a twisting configuration throughout the treatment period. There was no statistically significant difference between the survival curves of the two groups. Retrospective survival analysis was then performed on separate subgroups classified into the category of S1, S2, N1, and N2. The CQ + PSK group was better than the CQ alone group in its survival rate for the S1 + S2 (N1-2) group, the percentage being 11.5%, and a statistically significant difference was observed between the two groups (p = 0.089).

Adjuvants, Immunologic↗
PubMed1987

Electrostatic and hydrophobic interactions of the intermediate filament protein vimentin and its amino terminus with lipid bilayers.

Immunofluorescence and electron microscopical studies on the intracellular distribution of intermediate filaments (IFs) have demonstrated a close proximity of these cytoskeletal structures to cellular membranes. Moreover, nonepithelial IF (protein)s have been shown to exhibit high affinities for lipids, especially for negatively charged and nonpolar lipids. Here, using hydrophobic labeling with the photoactivatable phosphatidylcholine analogue [3H]1-palmitoyl-2-[11-[4-(trifluoromethyldiazirinyl]undecanoyl+ ++]-sn- glycero-3-phosphorylcholine or with 1-azidopyrene at low and physiological ionic strength, it is demonstrated that the IF subunit protein vimentin can interact with the hydrophobic core of lipid bilayers, in addition to strong ionic relationships between both reactants. Whereas the presence of acidic phospholipids in the lipid vesicles was absolutely essential for efficient vimentin labeling, cholesterol played a synergistic role in this reaction. Proteolytic degradation of photolabeled vimentin localized the derivatization exclusively to the non-alpha-helical, highly positively charged N-terminal domain of the filament protein. Furthermore, circular dichroism studies performed on the isolated N terminus of vimentin revealed a significant increase in the alpha-helical content of the polypeptide upon its interaction with vesicles containing negatively charged phospholipids. These results indicate an amphiphilic character of the N terminus and suggest that the cationic arginine residues of the N-terminal domain react with the negatively charged head groups of acidic phospholipids prior or parallel to interaction of the polypeptide with hydrophobic regions of the lipid bilayer.

Affinity Labels↗
PubMed1977

[Regression of a recurrent malignant glioma by combined chemoradiotherapy utilizing carboquone, FT-207 and telecobalt--report of a case (author's transl)].

Current chemotherapy of malignant brain tumor bases on cell kinetics. Chemotherapeutic agents are devided into two, cell cycle specific (CCS) and cell cycle non specific (CCNS) agents. A case of malignant glioma successfully treated by chemo-radiotherapy using a new combination of the two agents , Carboquone (CQ) as CCNS, which has not appeared in literature, and FT-207 as CCS is reported. A malignant glioma in the right frontal lobe in a case of 51-year-old male was removed subtotaly on Dec. 10th, 1971 in our clinic. Three years and five months after the surgery, the patient was diagnosed as having a recurred malignant glioma in the left frontal lobe from the clinical symptoms. This was supported by a positive brain scan and carotid angiography. A total dose of 57mg of CQ was continuously into the left internal carotid artery during two months. Simultaneously, 16g of FT-207 as a total dose was given orally and 4,550 rads of Telecobalt-60 were irradiated. One month after the beginning of these treatments, clinical symptoms improved obviously. Four months later, the size of the tumor shadow on the brain scan decreased remarkably and the shifted anterior cerebral artery returned to normal position on the carotid angiogram. Anemia, leucopenia, thrombocytopenia, nausea, and anorexia were the side-effects of these treatments. But these complications disappeared six weeks after the termination of the treatments.

Azirines↗
PubMed1987

Ciamexon in the low dose streptozotocin induced diabetes of mice.

This article is concerned with suppression of the development of diabetes experimentally induced by multiple injections of subdiabetogenic doses of streptozotocin (4 x 45 mg/kg/d) in mice (CD 1 and C57B16). Streptozotocin injections were followed by hyperglycemia and mononuclear cell infiltration of islets (insulitis). Ciamexon is a new immuno-modulating agent with promising effects in experimental models of autoimmune diseases and practically no toxic side effects. When Ciamexon was given before streptozotocin treatment blood glucose levels in the parenteral glucose tolerance test were suppressed in a dose dependent way. 60 days after streptozotocin application the percentage of islets showing insulitis or even necrosis was reduced in the Ciamexon treated group compared to the streptozotocin only group. In contrast, Cyclosporin A had a detrimental effect on diabetes in this model although blood levels were proved to be in the therapeutic range. From these results we conclude that Ciamexon should be tested for its effect in human type I diabetes.

Adjuvants, Immunologic↗
PubMed1987

Studies on the derivatives of aziridine. II. Synthesis and immunopharmacological analysis of substituted amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid.

Several new amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid were synthetized. The beta-/p-chlorobenzoyl/-acrylic acid 2 was used as the substrate. This compound was converted by reaction with appropriate amine into amides and anilides of beta-/p-chlorobenzoyl/-acrylic acid (3-10). These compounds react with ethylenoimine giving appropriate amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid (11-18). When pharmacologically analyzed, they appeared to possess marked immunotropic activity. The derivatives in question modulated both humoral as well as cellular immune response, the effect being related to the type of substitutent in the amide group.

Animals↗
PubMed1988

Sister chromatid exchange induction by diaziquone in human and mouse lymphocytes following both in vivo and in vitro exposures.

Diaziquone (AZQ) (NSC 182986), a lipid-soluble benzoquinone derivative currently being tested as an experimental chemotherapeutic agent, was used to treat mouse and human peripheral blood lymphocytes (PBLs) to determine its genotoxic potential by examination of sister chromatid exchange (SCE) induction. In vitro exposure to AZQ caused a linear increase in SCE in both mouse and human PBLs, with mouse PBLs being about twice as sensitive as the human cells. The lowest in vitro concentration found to induce a significant effect on SCE frequency was 0.3 micrograms/ml in mice and 1.0 micrograms/ml in human PBLs. Mice exposed by either i.p. or i.v. injection showed similar dose-related linear increases in SCE frequencies in their PBLs. After i.v. administration of AZQ, splenocytes from treated mice showed approximately the same SCE frequency as found in the PBLs. In general, AZQ caused a slowing of cell cycling in vivo while giving inconsistent responses in vitro. AZQ did cause a dose-related decrease in the number of recoverable mononuclear lymphocytes in mice treated in vivo. Contrary to the in vitro studies, comparison of SCE responses in mice with those previously observed in brain tumor patients undergoing chemotherapy with AZQ (Kligerman et al., Cancer Res., 47: 631-635, 1987) revealed AZQ was a much more potent SCE inducer in humans than in mice.

Animals↗
PubMed1988

Ca2+ binding effects on protein conformation and protein interactions of canine cardiac calsequestrin.

Calsequestrin is a Ca2+-binding protein located intraluminally in the junctional sarcoplasmic reticulum (SR) of striated muscle. In this study, Ca2+ binding to cardiac calsequestrin was assessed directly by equilibrium dialysis and correlated with effects on protein conformation and calsequestrin's ability to interact with other SR proteins. Cardiac calsequestrin bound 800-900 nmol of Ca2+/mg of protein (35-40 mol of Ca2+/mol of calsequestrin). Associated with Ca2+ binding to cardiac calsequestrin was a loss in protein hydrophobicity, as revealed with use of absorbance difference spectroscopy, fluorescence emission spectroscopy, and photoaffinity labeling with the hydrophobic probe 3-(trifluoromethyl)-3-(m-[125]iodophenyl)diazirine. Ca2+ binding to cardiac calsequestrin also caused a large change in its hydrodynamic character, almost doubling the sedimentation coefficient. We observed that cardiac calsequestrin was very resistant to several proteases after binding Ca2+, consistent with a global effect of Ca2+ on protein conformation. Moreover, Ca2+ binding to cardiac calsequestrin completely prevented its interaction with several calsequestrin-binding proteins, which we identified in cardiac junctional SR vesicles for the first time. The principal calsequestrin-binding protein identified in junctional SR vesicles exhibited an apparent Mr of 26,000 in sodium dodecyl sulfate-polyacrylamide gels. This 26-kDa calsequestrin-binding protein was greatly reduced in free SR vesicles and absent from sarcolemmal vesicles and was different from phospholamban, an SR regulatory protein exhibiting a similar molecular weight. Our results suggest that the specific interaction of calsequestrin with this 26-kDa protein may be regulated by Ca2+ concentration in intact cardiac muscle, when the Ca2+ concentration inside the junctional SR falls to submillimolar levels during coupling of excitation to contraction.

Animals↗
PubMed1988

[Complete change of the cell composition of the liver parenchyma following exposure to dipin and partial resection].

The phenomenon of total replacement of preexisting and damaged hepatocytes in mice were demonstrated by the method of autoradiography. Adult mice were injected an alkylating drug Dipin 2 h prior to partial hepatectomy and then proliferating cells were labelled by means of multiple injections of 14C-thymidine. Dipin in combination with mitotic stimulation induced multiple mitotic aberrations in proliferating hepatocytes resulting in degeneration, death and then elimination of prelabelled liver cells. New parenchymal tissue originated from non-labelled preneoplastic nodules. These hepatocyte nodules grew in size, propagated and 8-10 months later completely replaced the preexisting hepatocytes.

Alkylating Agents↗